TY  - JOUR
AU  - Paiva, Isabel
AU  - Jain, Gaurav
AU  - Lázaro, Diana F
AU  - Jerčić, Kristina Gotovac
AU  - Hentrich, Thomas
AU  - Kerimoglu, Cemil
AU  - Pinho, Raquel
AU  - Szegő, Èva M
AU  - Burkhardt, Susanne
AU  - Capece, Vincenzo
AU  - Halder, Rashi
AU  - Islam, Rezaul
AU  - Xylaki, Mary
AU  - Caldi Gomes, Lucas A
AU  - Roser, Anna-Elisa
AU  - Lingor, Paul
AU  - Schulze-Hentrich, Julia M
AU  - Borovečki, Fran
AU  - Fischer, André
AU  - Outeiro, Tiago F
TI  - Alpha-synuclein deregulates the expression of COL4A2 and impairs ER-Golgi function.
JO  - Neurobiology of disease
VL  - 119
SN  - 0969-9961
CY  - Orlando, Fla.
PB  - Academic Press
M1  - DZNE-2020-06539
SP  - 121-135
PY  - 2018
AB  - Alpha-synuclein (aSyn) is the major protein component of Lewy bodies and Lewy neurites, the typical pathological hallmarks in Parkinson's disease (PD) and Dementia with Lewy bodies. aSyn is capable of inducing transcriptional deregulation, but the precise effect of specific aSyn mutants associated with familial forms of PD, remains unclear. Here, we used transgenic mice overexpressing human wild-type (WT) or A30P aSyn to compare the transcriptional profiles of the two animal models. We found that A30P aSyn promotes strong transcriptional deregulation and increases DNA binding. Interestingly, COL4A2, a major component of basement membranes, was found to be upregulated in both A30P aSyn transgenic mice and in dopaminergic neurons expressing A30P aSyn, suggesting a crucial role for collagen related genes in aSyn-induced toxicity. Finally, we observed that A30P aSyn alters Golgi morphology and increases the susceptibility to endoplasmic reticulum (ER) stress in dopaminergic cells. In total, our findings provide novel insight into the putative role of aSyn on transcription and on the molecular mechanisms involved, thereby opening novel avenues for future therapeutic interventions in PD and other synucleinopathies.
KW  - Animals
KW  - Cells, Cultured
KW  - Collagen Type IV: biosynthesis
KW  - Collagen Type IV: genetics
KW  - Endoplasmic Reticulum: physiology
KW  - Gene Expression
KW  - Golgi Apparatus: physiology
KW  - Humans
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Mice, Transgenic
KW  - Peptide Fragments: biosynthesis
KW  - Peptide Fragments: genetics
KW  - alpha-Synuclein: biosynthesis
KW  - alpha-Synuclein: genetics
KW  - Col4a2 protein, mouse (NLM Chemicals)
KW  - Collagen Type IV (NLM Chemicals)
KW  - Peptide Fragments (NLM Chemicals)
KW  - Snca protein, mouse (NLM Chemicals)
KW  - alpha-Synuclein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:30092270
DO  - DOI:10.1016/j.nbd.2018.08.001
UR  - https://pub.dzne.de/record/140217
ER  -